The present invention relates to processes of manufacturing pioglitazone, which is a thiazolidinedione derivative, and salts thereof such as pioglitazone hydrochloride, and to compounds useful in the processes.
Some thiazolidinedione derivatives exhibit hypoglycemic activity and/or blood lipid lowering activity. They have been proposed for use in treating, inter alia, diabetes. Some of the well known and/or studied thiazolidinediones include pioglitazone, troglitazone, and rosiglitazone.
Pioglitazone, which is chemically 5-[[4-[2-(5-ethyl-2-pyridyl)-ethoxy]phenyl]methyl]-2,4-thiazolidinedione and corresponds to the formula (1)
is a commercially approved antidiabetic agent. Pharmaceutical compositions comprising pioglitazone, as the hydrochloride salt, are marketed under the brand name ACTOS® (Takeda Chemical Ind.) for treatment of type II diabetes.
Pioglitazone and its hydrochloride have been disclosed in EP 193256 and corresponding U.S. Pat. No. 4,687,777. In these patents, the thiazolidinediones, such as pioglitazone, can be formed by cyclizing an alpha-bromo acid ester (2) with thiourea. The resulting imino-thiazolidinone (3) is then hydrolyzed to make the corresponding glitazone. For pioglitazone, the reaction can be represented as follows:

The starting alpha-bromo acid ester (2) is taught to be prepared by Meerwein arylation. This process comprises preparing the corresponding aniline (4), diazotation thereof in the presence of hydrobromic acid, and coupling of the product of diazotation with an acrylic acid ester (5) under catalysis by cuprous oxide as shown on the scheme below:

However, forming the alpha-bromo acid ester by the Meerwein arylation reaction can be problematic. The sequence of reactions within this transformation must be controlled precisely. Otherwise the diazo-compound generated during the reaction can react with another nucleophile such as the bromide anion leading to a complicated outcome. Therefore, the reaction often gives a complicated result and lower chemical yield. Furthermore, acrylate esters (5) are toxic and irritating compounds.
Japanese published patent application 09-25273 deals with an improved method for making benzyl-thiazolidinones of a general formula (A)
from a phenyl lactate derivative (B)
The starting material (B) is taught to be prepared from the corresponding phenyl lactic acid by esterification and sulfonation. Schematically this can represented as follows:
However no method is given for making the starting phenyl lactic acid (D). Instead, the phenyl lactic acids exemplified in JP 09-25273, which include compounds where “X” is a pyridyl-containing moiety, are believed to be commercially available. While some phenyl lactic acids are commercially available, a phenyl lactic acid derivative needed to make pioglitazone, i.e. compound (D) where X is 5-ethyl-2-pyridylethyl group, is not known to be commercially available.
It would be desirable to find alternative processes for making thiazolidinediones such as pioglitazone. It would further be desirable to find an improved process for making pioglitazone from inexpensive and/or relatively easy to manufacture starting compounds without the need of a diazotation reaction.